In order for a virus to establish an infection, it must first enter a cell. Human immunodeficiency virus type 1 (HIV-1) infection, for example, involves binding of the viral envelope protein gp120/160 to cell surface CD4 molecules followed by interactions with a coreceptor. This results in fusion of the viral and cellular membranes. HIV-1 virus uptake can be reconstituted in heterologous cell lines by the co-expression of CD4 and the respective chemokine receptor, suggesting that cell-type and species specific infection is largely determined at the level mediated by the viral receptors.
The mechanisms by which other viruses enter cells are less well understood and no proper cell-based systems are available. For example, hepatitis C virus (HCV) is thought to bind to CD81 receptors expressed on the cell surface of hepatocytes via the structural protein E2, although the role of CD81 in mediating viral entry is controversial as CD81 is widely expressed on cell surfaces and thus, cannot explain virus tropism to hepatocytes. Moreover; in cell fusion assays that use chimeric HCV envelope proteins, over-expression of human CD81 has been shown not to affect cell fusion activity. For many viruses, the cellular receptors are even less well characterized.
The process of receptor-mediated endocytosis, by which cells internalize their plasma membrane together with molecules bound to cell surface receptors, have been implicated as the route of cell entry by several viruses including rabies, herpes, Semliki Forest, African swine fever and HIV viruses. However, it has been reported that CD81 has a poor internalization efficiency and this may be one of the reasons why CD81-overexpressing cells are only moderately permissive and can not be reproducibly infected by HCV.
Constitutively cycling receptors such as the transferrin receptor (TFR) and low density lipoprotein receptor (LDLR) are constitutively clustered in coated pits and can be rapidly internalized, transported to the acidic endosome and finally recycled back to the cell surface. The constitutive internalisation of such receptors is mediated by internalisation signals in their cytoplasmic domains. These internalisation signals are self-determined structural motifs that may confer recycling properties to proteins that are not normally endocytosed.